Topical montelukast for treatment of atopic dermatitis

ABSTRACT

A topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof, a gelling agent and water for the treatment of atopic dermatitis.

This application claims priority to the U.S. Provisional Pat. Application No. 62/331,528 filed on May 4, 2016, the disclosure of which is incorporated by reference herein.

BACKGROUND

Atopic dermatitis is an increasingly common pruritic, chronic, inflammatory skin disorder. There has been a striking rise in the incidence of Atopic dermatitis (AD) during the past two decades, which is not simply due to an increased recognition of the disease. Population studies suggest that in most countries, AD now affects at least 10-20% of children at some point during childhood. In particular, higher prevalence has been recorded in urban regions than in rural regions of development countries, and the disease is more common in higher social class groups, suggesting that environmental factors associated with more industrialized and urban living determine expression of AD.

There are pathogenic mechanisms that are in common to both AD and asthma. The exaggerated inflammatory response (including increased production of IgE and eosinophilia) to environmental triggers, including irritants and allergens is characteristic of both AD and asthma. Total IgE levels are elevated in both AD and asthma. Genetic studies have demonstrated common chromosomal linkages between AD and asthma.

Leukotrienes (LTs) are a class of potent biological inflammatory mediators derived from arachidonic acid through the 5-lipoxygenase pathway Leukotrienes are divided into two groups according to their chemical structure: those with a sulphur linkage (cysteinyl LTs: LTC₄, LTD₄, LTE₄), and those that lack one (LTB₄). Eosinophils, basophils and mast cells are the most important sources of LTs. Epidermal cells are able to transform neutrophil derived LTA₄ into LTB₄ and LTC₄. Thus the epidermis can also contribute significantly to LT synthesis. It has been shown that cysteinyl leukotrienes (cysLTs) mediate asthma and allergic rhinitis and when the LT receptors are antagonized, symptoms resolve. Leukotrienes are important pro inflammatory mediators that are capable of inducing airway smooth muscle constriction, airway hyper responsiveness, eosinophil migration, vascular permeability, edema, and chemotaxis. A role for LTs in AD has been suggested in the literature. There is evidence of enhanced LT production in the pathogenesis of AD. The cysteinyl LTs increase vascular permeability and dilate skin blood vessels. LTC₄ has been found in the skin of AD patients using the suction blister technique. Patients with AD have activated circulating basophils and increased basophil releasability of LTC₄. Cysteinyl LT release from basophils and eosinophils isolated from AD patients is increased compared to healthy controls. Enhanced spontaneous and stimulated release ability of LTC₄ from leukocytes of patients with AD compared with normal controls has been reported. Increased production of LTs has been reported in the skin of atopic patients after allergen specific challenge.

There are at least two types of LT receptors: cysLT1 and cysLT2. Montelukast (Singulair®, Merk-Frosst), zafirlukast (Accolate®, Zeneca), and pranlukast (Ultair®, SmithKline Beecham) are LT receptor antagonists that demonstrate high-affinity binding to the cysLT1 receptor. Montelukast is currently indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older and for the relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older. Montelukast is generally a safe drug during long term treatment; side effects are minimal. Asthma and allergic rhinitis have numerous pathophysiological elements in common with AD, and together these three diseases are referred to as the “atopic triad”. As outlined above there are pathogenic mechanisms that are central to both AD and asthma. Evidence in the literature provides a pathophysiological rationale for the use of cysLT receptor blockers in the treatment of AD however the exact mechanism of action of leukotriene receptor antagonists in AD is not known. Intradermal LTD₄ causes a wheal-and-flare response that could be blocked by a LTD₄ antagonist. Montelukast has been shown to decrease eosinophils by 15%.LTD₄ stimulates proliferation of eosinophil hematopoietic progenitor cells, and this increase can be suppressed by Montelukast.

The major function of the skin is to protect the body against physical and chemical injury and to prevent loss of body water and other substances. The stratum corneum (SC) is the outmost layer of the skin which is being continually replaced. By so doing the skin is well adapted to its requirements for repairing damage from wear and tear. However, in Atopic Dermatitis environmental and individual factors interact in a complex manner to induce skin abnormalities and dryness. Application of moisturizers to the skin induces changes in its superficial as well as deep layers. The chemical and physical characteristics of the individual ingredients of the formulation determine the performance of the drug product.

Moreover, in topical treatments of dermatological conditions the efficacy is likely to depend on the dosage, where compliance is a great challenge faced in the management of the diseases.

Montelukast sodium exerts additional challenge to be formulated in a semi solid formulation even for experienced formulators.

Sodium montelukast (Singulair), chemically known as [sodium 1-(1-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)-phenyl)(3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)-methyl)-cyclo-propane) acetate is a photosensitive compound requiring special handling precautions to protect specimens from light especially in a solution.

In the montelukast molecule there are number of functional groups that impair the chemical stability of this substance. Montelukast is known to be prone to the formation of several types of impurities:

-   1. a sulfoxide impurity:     [1-[((RS)[1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl)phenyl)-3-[2-(1-hydroxy-1-methylethyl)phenyl)propyl]sulfinyl]methyl]cyclopropyl]acetic     acid; -   2. a diol impurity:     2-(2-(3-(S)-(3(E)-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol; -   3. a methyl styrene impurity:     [1-[[[(1R)-1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyL[]phenyl]-3-[2-(1-methylethenyl)phenyl]propyl]sulfanyl]melhyl]cyclopropyl]     acetic acid (USP imp F); -   4. a cis-isomer impurity:     [1-[[[(1R)-1-[3-[(Z)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]     acetic acid; -   5. a Michael adduct impurity (1):     1-[[((1R)-1-[3-[(1R)-1[[[1-(Carboxymethyl)cyclapropyl]methyl]sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]     propyl]suifanyl]methyl]cyclopropyllacetic acid; -   6. a Michael adduct impurity (2):     1-[[[(1R)-1-[3-[(1S)-1-[[[1-(Carboxymethyi)cyclopropyl]methyl]sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]     propyl]sulfanyl]methyl]cyclopropyl] acetic acid; -   7. a methyl ketone impurity:     [1-({((1R)-3-(2-acetylphenyl)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl]propyl]     sulfanyl]methyl]cyclopropyl]acetic acid.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a topical formulation comprising 1-(1-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)-phenyl)(3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl) thio)-methyl)-cyclo-propane) acetate (montelukast) or a pharmaceutically acceptable salt thereof, a gelling agent and water for the treatment of atopic dermatitis .

In one aspect, the present invention provides a topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof and at least one oil for the treatment of atopic dermatitis wherein the formulation is waterless.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 describes the % Clinical Score (Erythema, Excoriation/Erosion, Scaring/Dryness and Total Cumulative) compared to Disease Control after Montelukast Topical Gel (Example 1) (RD#14152) Treatment (from day 6 to 14) in DNCB-induced Atopic Dermatitis in Balb/c Mice on day 15, n=10

FIG. 2 - Photographs (representative) of Animal’s Back Skin after Montelukast Topical cream (Example 14) and Montelukast Topical Gel Treatment (Example 1) (from day 6 to 14) in DNCB-induced Atopic Dermatitis in Balb/c Mice on day 15, n=10

FIG. 3 describes the Levels of Cytokines (IL-4, TNF-α and IFN-Y) ng/gm of Protein in Back Skin Homogenate after Montelukast Topical Cream (Example 14, RD#14153) and Montelukast Topical Gel (Example 1, RD#14152) Treatment (from day 6 to 14) in DNCB-induced Atopic Dermatitis in Balb/c Mice on day 15, n=10

FIG. 4 -Images (representative) of Ki67 Immunohistochemistry of Back Skin section at 100X magnification after Montelukast Topical Cream (Example 14, RD # 14153) and Montelukast Topical Gel (Example 1, RD#14152) Treatment (from day 6 to 14) in DNCB-induced Atopic Dermatitis in Balb/c Mice on day 15, n=10

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof, a gelling agent and water for the treatment of atopic dermatitis .In certain embodiments the salt is an alkali metal salt, such as sodium or potassium; an alkaline earth salt; or an ammonium salt.

Furthermore, the term “montelukast” as used herein encompasses polymorph crystal forms and any other form of montelukast that has one or more of the pharmaceutical activities of montelukast.

In certain embodiments, the topical formulation may comprise about 0.01% w/w to about 10%w/w montelukast or a pharmaceutically acceptable salt.

In certain embodiments, the concentration of montelukast or a pharmaceutically acceptable salt in the topical formulation is between about 0.5 %w/w to about 5 % w/w.

In certain embodiments, the concentration of montelukast or a pharmaceutically acceptable salt in the topical formulation is between about 5 %w/w to about 10 %w/w

In preferred embodiments, the concentration of montelukast or a pharmaceutically acceptable salt in the topical formulation is 5 %w/w.

In one embodiment of the present invention, the topical formulation of montelukast or a pharmaceutically acceptable salt can be a gel. In one embodiment, a gel may be prepared by providing a gelling agent and adding an excipient such as water in case of a hydrous gel. The gel may include a variety of additional components such as, but not limited to solvents, emulsifiers, thickeners, stabilisers, gelling agents, chelating agents, surfactants, emollients, permeation enhancers, preservatives, antioxidants, lubricants, pH adjusters.

In one embodiment, the topical formulations of Montelukast or a pharmaceutically acceptable salt thereof provide topical penetration of the active agent through the epidermis and into the dermis.

In some embodiments, the topical formulations described above comprise penetration enhancers, which facilitate the penetration of the active agent and preferably dissolve the active ingredient present in the formulations of the invention

There are numerous penetration enhancers that can be used in accordance with the present invention. Various useful permeation enhancers include, for example: polyols and esters, including polyethylene glycol, polyethylene glycol monolaurate, and butanediol; sulfoxides, including dimethylsulfoxide and decylmethylsulfoxide; ethers, including diethylene glycol monoethyl ether (e.g., Transcutol.RTM. P) and diethylene glycol monomethyl ether; fatty acids, including lauric acid, oleic acid, and valeric acid; fatty acid esters, including isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; nitrogenous compounds including urea, dimethyl acetamide, dimethylformamide 2-pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, and triethanolamine; terpenes; alkanones; organic acids, including salicylic acid, citric acid, and succinic acid; and any mixtures thereof. A penetration enhancer can be used in concentrations ranging from about 1-15% by weight, preferably about 2-12% by weight, and more preferably about 3-10% by weight, of the total composition.

In certain embodiments of the invention, the pH of the topical gel formulation of montelukast or a pharmaceutically acceptable salt is less than 6. Typically the pH is in the range from 4 to 6. In a more preferred embodiment, the pH is in the range of 5 to 6.

In one embodiment of the present invention, the topical formulation of montelukast or a pharmaceutically acceptable salt may comprise a gelling agent. Examples of suitable gelling agents for use in the present invention may include, but are not limited to hyaluronic acid and its salts such as Sodium Hyaluronate, cellulose derivatives such as hydroxypropyl cellulose (HPC), Hydroxyethyl cellulose (Natrosol 250 HEC HHX), carbomers such as sodium carbomer.

In one embodiment, suitable topically acceptable solvents may also be used in the topical composition. Suitable topically acceptable solvents for use in the present invention include, but are not limited to lower alcohols, ethanol, isopropanol, benzyl alcohol, propanol, methanol, other C4-C10 mono alcohols and mixtures thereof. In another embodiment, the solvents suitable for use in the formulation of the present invention may include albumin, gelatin, citric acid, ethylenediaminesodiumtetraacetate, dextrin, dimethylsulfoxide, dimethylacetamide, dimethylformamide, 2-pyrrolidone, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, I-dodecylazacycloheptan-2-one and other n-substituted-alkyl-azacycloalkyl-2-ones(azones), sodium hydrosulfite and mixtures thereof. In some embodiments, the topical formulation of the invention comprises a polar aprotic solvent, preferably selected from anyone or more of the following: dimethylsulfoxide, dimethyl acetamide, dimethylformamide or N-methylpyrrolidone.

In another embodiment of the present invention, the topical formulation of montelukast or a pharmaceutically acceptable salt may further comprise an antioxidant such butylated hydroxy anisole or butylated hydroxy toluene; preservatives such as a paraben which include a methyl paraben or propyl paraben.

In one aspect of the invention, the topical formulation of montelukast or a pharmaceutically acceptable salt may comprise a triglyceride. In a preferred embodiment, if a triglyceride is present, it may be a medium chain triglyceride (MCT) of e.g. hexanoic acid; octanoic acid; decanoic acid or dodecanoic acid.

In certain embodiments, the topical formulation described above comprises an occlusive ingredient, such as petroleum jelly/white petrolatum; a wax; an oil; a silicone; a film forming polymer, such as hyaluronic acid, hydroxypropyl cellulose (HPC) or a poly (meth) acrylate, (e.g. Eudragit®); or any combination thereof, and said formulation is therefore an occlusive formulation.

The pharmaceutically acceptable inactive ingredients of the formulation described above may further comprise an oil, such as castor oil or a castor oil derivative(e.g. trihydroxystearin), fractionated coconut oil, or olive oil; an occlusive ingredient, such as petroleum jelly/white petrolatum, a wax, an oil, a silicone, glycerin; an MCT of e.g. hexanoic acid, octanoic acid, decanoic acid or dodecanoic acid; an antioxidant, such as butylated hydroxyanisole; or any combination thereof.

The topical formulation described above may comprise a colloidal solution/suspension, wherein the active agent is in the form of microparticles that are suspended in said formulation, i.e. particles having a diameter of about 1-100 µm. Alternatively, the topical formulation may comprise a microparticle or nanoparticle comprising or encapsulating the active agent, wherein said microparticle or nanoparticle is selected from the group consisting of (a) a solid lipid nanoparticle; (b) a liposome; and (c) a polymeric microparticle or nanoparticle.

In certain embodiments, the solid lipid nanoparticle comprises a lipid selected from the group consisting of cholesterol, a triglyceride, a phospholipid, a fat and a wax.

In certain embodiments, the solid lipid nanoparticle or liposome comprises a phospholipid selected from the group consisting of a lecithin, such as egg or soybean lecithin; a phosphatidylcholine such as egg phosphatidylcholin; a hydrogenated phosphotidylcholine; a lysophosphatidylcholine; dipalmitoylphosphatidylcholine; distearoylphosphatidylcholine; dimyristoylphosphatidylcholine; dilauroylphosphatidylcholine; a glycerophospholipid such as phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol phosphate, phosphatidylinositol bisphosphate and phosphatidylinositol triphosphate; sphingomyelin; cardiolipin; a phosphatidic acid; a glycolipid such as a glyceroglycolipid, e.g. a galactolipid and a sulfolipid, a glycosphingolipid, e.g. a cerebroside (a glucocerebroside and a galactocerebroside), and a glycosylphosphatidylinositol; a plasmalogen; a phosphosphingolipid such as a ceramide phosphorylcholine, a ceramide phosphorylethanolamine and a ceramide phosphorylglycerol; and a mixture thereof.

The phospholipid may further be admixed with one or more nonphosphorous-containing molecules selected from the group consisting of a fatty amine, such as octylamine, laurylamine, N-tetradecylamine, hexadecylamine, stearylamine, oleylamine, tallow amine, hydrogenated tallow amine, and cocoamine; a fatty acid; a fatty acid amide; an ester of a fatty acid such as isopropyl myristate, hexadecyl stearate, and cetyl palmitate; cholesterol; a cholesterol ester; a diacylglycerol; a glycerol ester, such as glycerol ricinoleate; and a mixture thereof.

In certain embodiments, the polymeric microparticle or nanoparticle comprises a polymer selected from the group consisting of a silicone; poly(lactic-co-glycolic acid (PLGA);polylactic acid (PLA); chitosan; gelatine; ethylcellulose; polycaprolactone; a polyalkyl cyanoacrylate; and any combination thereof.

In any one of the topical formulations described above, if a triglyceride is present, it may be a medium chain triglyceride (MCT) of e.g. hexanoic acid; octanoic acid; decanoic acid or dodecanoic acid.

The topical formulations described above provide topical penetration of the active agent through the epidermis and into the dermis.

In some embodiments, the topical formulations described above comprise penetration enhancers, which facilitate the penetration of the active agent and preferably dissolve the active ingredient present in the formulations of the invention.

In certain embodiments, the topical gel formulation comprises

Category of ingredient Active (Montelukast or a salt thereof) Water miscible organic solvent Penetration enhancer Antioxidant Chelating Agent Water Preservative Gelling agent

The gel formulation may also comprise pH adjusting agents and occlusive agents. The concentration of above category of ingredient/ingredients may be determined based on knowledge by the person skill in the art.

Examples of specific gel formulation include:

(a) Formula 1 Category Ingredient % W/W Active Montelukast sodium 5.00 Water miscible organic solvent Alcohol 96% 25.00 Penetration enhancer DMSO 10.00 Antioxidant BHT 0.10 Chelating Agent EDTA 0.10 Water Purified water 57.90 Preservative Methyl paraben 0.30 Preservative Propyl paraben 0.10 Gelling agent Hydroxyethylcellulose (M_(w) 90,000 to 1,300,000) 1.50 pH adjusting agent HCl (10% solution) q.s.

b) Formula 2 Category of ingredient Ingredient % W/W Occlusive ingredient Dimethicone 1 Occlusive ingredient Cyclomethicone 4 Active Montelukast sodium 3 Emulsifier Silicone Glycerol emulsifier 1.5 Occlusive ingredient Cetearyl Ethylhexanoate 2.5 Water miscible organic solvent Glycerin 3.0 Solvent Water Up to 100 Gelling agent Sodium Carbomer 2.5 Lubricant Sodium Hyaluronate 1.0

c) Formula 3 Ingredient % W/W Montelukast sodium 1% Alcohol 25% BHT 0.10% Purified water 60.00 DMSO 10.00% Methyl paraben 0.30% Propyl paraben 0.10% Carbopol 947P (polymers of acrylic acid) 0.40% EDTA 0.10% Sepineo 600 (Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3%

d) Formula 4 Category of ingredient Ingredient % W/W Active Montelukast sodium 1% Water miscible organic solvent Alcohol 25% Antioxidant BHT 0.10% Water Purified water 60.00 Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 0.40% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 (Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3% pH adjusting agent Citric acid buffer To pH 5.6

e) Formula 5 Category of ingredient Ingredient % W/W Active Montelukast sodium 1% Water miscible organic solvent Alcohol 25% Antioxidant BHT 0.10% Water Purified water 60.00 Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 0.40% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 ( Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3% pH adjusting agent Phosphate Buffer pH 5.6

In one embodiment, the present invention relates to a topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof, at least one oil for the treatment of atopic dermatitis wherein the formulation is waterless.

In one embodiment of the present invention, the waterless topical formulation comprising Montelukast or a pharmaceutically acceptable salt may further a topically acceptable solvent and an amphiphilic compound.

In another embodiment, the waterless formulation may be an ointment. In another embodiment, the waterless formulation may be a solution. In another embodiment, the waterless formulation may be a gel. The waterless formulations may include a variety of additional components such as, but not limited to solvents, emulsifiers, chelating agents, surfactants, emollients, permeation enhancers, preservatives, antioxidants, lubricants, pH adjusters.

In one embodiment, the ointment may comprise an amphiphilic compound. The examples of suitable amphiphilic compounds include, but are not limited to vegetable oils, animal fats, and semisolid hydrocarbons obtained from petroleum.

In one embodiment, examples of amphiphilic compound include polypropylene glycol -15 stearyl ether, propylene glycol monostearate (monosteol), Poloxylhydrogenated Castor oil, oleyl alcohol, polyoxyglycerides, propylene carbonate

Examples of oils, such as poloxylhydrogenated castor oil (e.g. trihydroxystearin), fractionated coconut oil, or olive oil; an occlusive ingredient, such as petroleum jelly/white petrolatum, a wax, an oil, a silicone, glycerin; an MCT of e.g. hexanoic acid, octanoic acid, decanoic acid or dodecanoic acid; lubricants such as Cyclomethicone and Dimethicone 5225C, Cyclomethicone, polypropylene glycol -15 stearyl ether, ; an antioxidant, such as butylated hydroxy anisole or butylated hydroxyl toluene; or any combination thereof.

In certain embodiments, the topical formulation may comprise an occlusive ingredient selected from the group of siloxanes such as cyclomethicone, dimethicones; petroleum jelly/ white petrolatum.

In one aspect of the invention, the topical formulation of montelukast or a pharmaceutically acceptable salt may comprise a triglyceride. In a preferred embodiment, if a triglyceride is present, it may be a medium chain triglyceride (MCT) of e.g. hexanoic acid; octanoic acid; decanoic acid or dodecanoic acid.

In certain embodiments, the topical waterless formulation comprises:

Category of ingredient Active (Montelukast or a salt thereof) Water miscible organic solvent Amphiphilic compound Occlusive ingredient Oil Antioxidant

The gel formulation may further comprise a gelling agent.

The concentration of above category of ingredient/ingredients may be determined based on knowledge by the person skill in the art.

In one embodiment, the waterless formulation of montelukast or a pharmaceutically acceptable salt can be:

a solution comprising

Category of Ingredient Ingredient % W/W Topically acceptable solvent Alcohol (Dehydrated) 34.5 Amphiphilic compound Poloxylhydrogenated Castor 2.5 Active Montelukast sodium 3 oil Fractionated Coconut oil 60

or a gel formulation comprising

Category of ingredient Ingredient % W/W Topically acceptable solvent Alcohol (Dehydrated) 31 Amphiphilic compound Poloxylhydrogenated Castor 2.5 Active Montelukast sodium 3 oil Fractionated Coconut oil 60 Gelling agent Hydroxy propyl cellulose 3.5

or an ointment comprising

Category of ingredient Ingredient % W/W Active Montelukast sodium 0.5-5 Occlusive ingredient Petroleum jelly/white petrolatum 80 Oil Trihydroxystearin 1 -3 oil Olive oil 12- 18.5

or an ointment comprising

Category of ingredient Ingredient % W/W′ Active Montelukast sodium 0.5-5 Water miscible organic solvent Glycerine 65-75 Oil Medium chain triglycerides 20 Antioxidant Antioxidant 0-0.5

or an ointment comprising

Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient Cyclomethicone 94.52 Amphiphilic compound Cyclomethicone and Dimethicone 0.40

or an ointment comprising

Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient Petrolatum White 55.92 Amphiphilic compound PPG-15 Stearyl Ether 16 Oil Medium Chain Triglycerides 20 Amphiphilic compound Monosteol 3

API is milled to <5 micron size. Homogenous distribution of crystals in ointment was observed or an ointment comprising

Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient/ Petrolatum White 49.92 Oil Mineral Oil 45

In certain embodiments, each one of the topical formulations described above further comprises an additional active agent, such as an anti-pruritic agent, such as pramoxine; an antihistamine; an anti-inflammatory agent, such as a corticosteroid (e.g. hydrocortisone or desoximetasone), or a glucocorticosteroid; an antibacterial agent, such as dapson (diaminodiphenyl sulfone) or minocycline; a vitamin, such as vitamin B, C, D or E; a non-steroidal anti-inflammatory drug (NSAID); a peripheral analgesic agent; or a different leukotriene receptor antagonist, such as zafirlukast or pranlukast, or a pharmaceutically acceptable derivative thereof.

In another aspect, the present invention provides a topical formulation comprising a pharmaceutically acceptable carrier and a microparticle(s) or nanoparticle(s) comprising an active agent selected from the group consisting of a leukotriene receptor antagonist, such as an antagonist specific to cysLT 1, and a pharmaceutically acceptable derivative thereof.

The active agent may be montelukast, zafirlukast or pranlukast, or a pharmaceutically acceptable derivative thereof. In certain embodiments the active agent is montelukast, e.g. montelukast sodium. The microparticles or nanoparticles of this topical formulation may be as defined above.

In certain embodiments, each one of the topical formulations described above is formulated as a gel, solution, suspension, lotion, paste, cream, ointment, aerosol, dusting powder or a patch.

In an additional aspect, the present invention provides a topical formulation for use in the treatment of atopic dermatitis, wherein said topical formulation is any one of the topical formulations defined herein above.

In a further aspect, the present invention is directed to a method for the treatment of atopic dermatitis in a patient in need thereof, comprising administering to the patient any one of the topical formulations defined herein above.

In certain embodiments, the use or method comprises topically exposing the patient to said formulation once or twice daily; for example, the use or method comprises exposing the patient to a formulation that comprises about 0.5% to about 5% montelukast sodium.

In case the topical formulation comprises microparticles or nanoparticles encapsulating the active agent, they provide targeting of the active agent to hair follicles.

In certain embodiments, the topical formulation described above comprises a formulation selected from the group consisting of:

(a) a solid lipid nanoparticle (SLN) dispersion comprising Ingredient % W/W Montelukast sodium 2.0 Emulsifiers (e.g. Poloxamerl88/polysorbate 20) 0.75 Lipids/Hard fat/Triglycerides (e.g. Compritol, Cocoa butter, Phosphatidylcholine) 15 Water Up to 100

-   (b) a liposomal formulation comprising Sphingomyelin/ cholesterol     e.g. in the molar ratio of 2:1 ;phosphatidyl choline/cholesterol     e.g. in the molar ratio of 3:1 ;phosphatidyl     ethanolamine/phosphatidyl choline/ cholesterole.g. in the molar     ratio of 3:4:2 as representative examples; and -   (c) a formulation of polymeric nanocapsules based on a polymer     selected from the group consisting of a silicone;     poly(lactic-co-glycolic acid (PLGA);polylactic acid (PLA); chitosan;     gelatine; ethylcellulose; polycaprolactone; a polyalkyl     cyanoacrylate and any combination thereof.

In certain embodiments, in the topical formulation comprising encapsulating nanoparticles, the particles have a size (diameter) of up to about 1000 nm.

EXAMPLES Example 1

Montelukast in a gel formulation Category Ingredient % W/W Active Montelukast sodium 5.00 Water miscible organic solvent Alcohol 96% 25.00 Penetration enhancer DMSO 10.00 Antioxidant BHT 0.10 Chelating Agent EDTA 0.10 Water Purified water 57.90 Preservative Methyl paraben 0.30 Preservative Propyl paraben 0.10 Gelling agent Hydroxyethylcellulose (M_(w) 90,000 to 1,300,000) 1.50 pH adjusting agent HCl (10% solution) q.s.

Example 2

Montelukast in a gel formulation Category of ingredient Ingredient % W/W Occlusive ingredient Dimethicone 1 Occlusive ingredient Cyclomethicone 4 Active Montelukast sodium 3 Emulsifier Silicone Glycerol emulsifier 1.5 Occlusive ingredient Cetearyl Ethylhexanoate 2.5 Water miscible organic solvent Glycerin 3.0 Solvent Water Up to 100 Gelling agent Sodium Carbomer 2.5 Lubricant Sodium Hyaluronate 1.0

Example 3

Montelukast in a gel formulation Category of ingredient Ingredient % W/W Active Montelukast sodium 1 % Water miscible organic solvent Alcohol 25% Antioxidant BHT 0.10% Water Purified water 60.00 Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 0.40% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 (Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3% pH was adjusted to 5.6 with citric/phosphate buffer

Example 4

Montelukast in a gel formulation Category of ingredient Ingredient % W/W Active Montelukast sodium 5% Water miscible organic solvent Alcohol 22.4% Antioxidant BHT 0.10% Water Purified water 56.00 Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 3% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 ( Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3% Crystals of montelukast are present in the formula

Example 5: Montelukast in a Gel Formulation

Category of ingredient Ingredient % W/W Active Montelukast sodium 3% Water miscible organic solvent Alcohol 22.4% Antioxidant BHT 0.10% Water Purified water 57.5% Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 1.5% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 ( Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3% pH adjusting agent Phosphate buffer or citrate buffer pH adjusted to 5.6 Crystals of montelukast are present in the formula

To protect montelukast from light and increase its stability particulate drug carriers can be formulated (e.g. oil in water or water in oil emulsions, liposomes, microparticles and nanoparticles of polymers (synthetic or natural), solid lipid nanoparticles in which sodium montelukast is encapsulated (dissolved or suspended))

Waterless formulations in which sodium montelukast can be dissolved or suspended are another route for preparation of stable formulations. Typically the waterless formulations contain at least one oil.

Example 6: Non Aqueous Solution Formulation (Waterless Formulation)

Category of Ingredient Ingredient % W/W Topically acceptable Alcohol (Dehydrated) 34.5 Amphiphilic compound Poloxylhydrogenated Castor 2.5 Active Montelukast sodium 3 oil Fractionated Coconut oil 60

Example 7: Ointment (Waterless Formulation)

Category of ingredient Ingredient % W/W Active Montelukast sodium 0.5-5 Occlusive ingredient Petroleum jelly/white petrolatum 80 Oil Trihydroxystearin 1 -3 oil Olive oil 12- 18.5

Example 8 : Ointment (Waterless Formulation)

Category of ingredient Ingredient % W/W′ Active Montelukast sodium 0.5-5 Water miscible organic solvent Glycerine 65-75 Oil Medium chain triglycerides 20 Antioxidant Antioxidant 0-0.5

Example 9: Ointment (Waterless Formulation)

Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient Petrolatum White 55.92 Amphiphilic compound PPG-15 Stearyl Ether 16 Oil Medium Chain Triglycerides 20 Amphiphilic compound Monosteol 3

Example 10: Ointment (Waterless Formulation)

Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient/ Petrolatum White 49.92 Oil Mineral Oil 45 Crystals of less than 5 micron are homogenously dispersed in the ointment formulation

Example 11: Colloidal Particle Formulation/ SLN (Solid Lipid Nanoparticle) Dispersion

Ingredient % W/W Montelukast sodium 2.0 Emulsifiers (Poloxamer188/polysorbate 20) 0.75 Lipids/Hard fat/Triglicerides (Compritol, Cocoa butter, Phosphatidylcholine) 15 Water Up to 100 Colloidal gel formulation of polymeric nanocapsules

Various techniques can be used to produce polymer nanoparticles in which montelukast would be encapsulated, such as solvent evaporation, salting-out, dialysis, supercritical fluid technology, micro-emulsion, nano-emulsion, surfactant-free emulsion, and interfacial polymerization. The choice of method depends on a number of factors, such as, particle size, particle size distribution, area of application, etc.

The produced polymeric nanoparticles would be suspended in a cream or a gel formulation. Typical polymers that are in use for the production of pharmaceutical nanoparticles are silicon, PLGA, PLA, chitosan, gelatine, ethylcellulose, polycaprolactone and poly alkyl cyanoacrylates.

Example 12: Lipid Nano Emulsion

Ingredient % W/W Soybean oil 10-20 Lecithin 1 Glycerol 2 Montelukast 1 Water Up to 100

Example 13: Solution Formulation (Substantially Anhydrous)

Ingredient % W/W Montelukast sodium 5% Alcohol (96%) 66.45 BHT 0.1% Propylene glycol 28.45

Example 14: Montelukast in a Cream Formulation

Ingredient % W/W Montclukast sodium 5% Propylene glycol 10% DMSO 10% Methylparaben 0.3% Propylparaben 0.1% BHT 0.1% MCT 10% Glyceryl Stearate & PEG-100 Stearate 5% Purified water 59.1% Natrosol 250 HEC HHX 0.30% EDTA 0.1% HCl (10% sol) q.s. Crystals of montelukast are present in the formula

Example 15. Animal Model of Atopic Dermatitis With Repeated DNCB Patch in BALB/c Mice

The following is the animal model which is being used to test the efficacy of the formulation of the present invention for atopic dermatitis. Repeated 2,4-dinitrochlorobenzene, (DNCB) applications is a common animal model of AD which possesses benefits of reproducibility.

Montelukast sodium topical gel (Example 1, RD#14152) and Montelukast sodium topical cream (Example 14, RD#14153) formulations for the treatment of Atopic dermatitis (Efficacy studies).

Balb/c mice were used for the study. The animals were sensitized on Day 1 by application of 100µl of 1% DNCB in acetonc : olive oil (Figaro) 3:1 on shaved dorsal back skin and 10µl of 1% DNCB on right ear from day 1 to day 4. On day 6, animals were weighed using digital weighing balance.

After 4 hr of treatment, animals were challenged by application of 100µl of 0.5% DNCB in acetone : olive oil (3:1) on dorsal back skin and 20 µL of 0.5% DNCB on right ear on day 8, day 10, day 12, day 14. Normal control animals were sensitized and challenged with acetone and olive oil alone. 200 mg of Montelukast sodium topical gel and Montelukast sodium topical cream were topically applied in around 5-6 cm² area on the back skin of the mice for 9 days from day 6 to day 14. Respective placebo items were topically applied in around 5-6 cm2 area on the back skin of the mice for 9 days from day 6 to day 14. Bethametasone valerate cream was used as the reference item 0.40 mg of reference item was applied topically per animal on the back skin for 9 days from day 6 to day 14. All the vials of test items were opened and test items were topically applied under yellow sodium lamp light. The animals were kept under yellow sodium lamp light up to 4 hours after application.

In one embodiment of the present invention, clinical scoring has been performed to determine the efficacy of tested formulations with appropriate controls as a part of the study. On day 15, back skin severity scores were assessed as following criteria 1) Erythema (0-3), 2) Excoriation/Erosion (0-3), 3) Scarring/ Dryness in each symptoms was scored by following criteria no lesion, 0; mild, 1; moderate, 2; severe, 3. Total maximum cumulative score was 9 as defined as the sum of these individual scores.

TABLE 1 Erythema (0-3), Excoriation/Erosion (0-3), Scaring/Dryness (0-3) and Total Cumulative Score (0-9) after Montelukast Topical Cream (Example 14, RD # 14153) or Gel (Example 1, RD # 14152) Treatment (from day 6 to 14) in DNCB-induced Atopic Dermatitis in Balb/c Mice on day 15, n=10 Group No Dose Groups MEAN ± SEM Erythema Excoriation/ Erosion Scarring/ Dryness Total cumulative score 1 Normal Control 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 2 Disease Control 2.70 ± 0.21*** 1.60 ± 0.27*** 1.70 ± 0.15*** 6.00 ± 0.45*** 3 Placebo of Montelukast Sodium gel of Example 1 2.40 ± 0.16 1.60 ± 0.27 1.90 ± 0.10 5.90 ± 0.43 4 Montelukast sodium gel of Example 1 2.10 ± 0.18 0.80 ± 0.25^($) 1.70 ± 0.15 4.60 ± 0.43^($) 5 Placebo of Montelukast Sodium cream of Example 14 2.20 ± 0.25 1.20 ± 0.20 1.90 ± 0.10 5.30 ± 0.30 6 Montelukast sodium cream of Example 14 2.40 ± 0.16 1.40 ± 0.27 2.20 ± 0.20 6.00 ± 0.45 7 Betamethasone valerate cream IP 1.20±0.20^(###) 1.20 ± 0.25 1.70 ± 0.15 4.10 ± 0.28^(###) Data were analyzed by 2-tailed Student’s t-test

-   Normal Control vs Disease control group (*=p<0.05, **=p<0.01,     ***=p<0.001) Disease control group vs Betamethasone Valerate cream     (#=p<0.05, -   ##=p<0.01,###=p<0.001) -   Placebo of Montelukast Sodium gel vs Montelukast Sodium gel     ($=p<0.05, $$=p<0.01, $$$=p<0.001) -   Placebo of Montelukast Sodium cream vs Montelukast Sodium cream     (@=p<0.05, -   @ @=p<0.01, @ @ @-p<0.001).

As seen in Table 1, there was a significant increase in erythema, excoriation, dryness and total cumulative score in disease control group (DNCB) as compared to the normal control group. Montelukast sodium topical gel showed significant inhibition in excoriation as compared to its placebo. Also, the excoriation / erosion score of Montelukast sodium topical gel was lower than that of the Betamethasone valerate cream indicating that the gel reduced the excoriation or the erosion more than the Bethametasone valerate cream. A significant inhibition in the total cumulative score of Montelukast sodium topical gel was seen as compared to its placebo. Betamethasone valerate cream showed significant inhibition in erythema and total cumulative score but did not show significant inhibition in excoriation as compared to the disease control group.

In one embodiment of the present invention, the % clinical score (Erythema, Excoriation/erosion, Scarring/dryness and Total cumulative) of the disease control group, the placebo groups, Montelukast sodium topical cream group and the Montelukast sodium topical gel group were compared.(FIG. 1 ). As seen in FIG. 1 , the % clinical score of Montelukast sodium topical gel for erythema was lower i.e 78% as compared to the disease control which showed a score of 100%. The % clinical score of the gel for erythema was also lower as compared to its placebo. Bethametasone valerate cream showed a % clinical score of 100% which was lower among all the treatment groups. Montelukast sodium topical gel group showed 50% clinical score for excoriation/erosion as compared to its placebo, the disease control, the montelukast sodium topical cream group and its placebo and the Bethametasone valerate cream group. The total cumulative score of the group treated with Montelukast sodium topical gel was 77% as compared to the disease control and the placebo group. Montelukast sodium topical gel was effective for erythema as compared to the placebo and the disease control groups. (FIG. 2 )

In one embodiment of the present invention, DNCB induced atopic dermatitis of the skin in mice reproduces biochemical and histopathological parameter characteristic of atopic dermatitis in humans.

Tissue collection- The animals were sacrificed by CO₂ asphyxiation. The back skin was collected and was preserved in 50ml falcon tube containing 10% formalin for histologic analysis or was stored in micro centrifuge tube at -70° C. for cytokine analysis.

Cytokine estimation- For determination of cytokines levels, the skin samples were removed from -70° C. and kept on ice. The 20% w/v tissue homogenate was prepared by adding cocktail protease inhibitor to the tubes containing weighed skin tissues. The skin tissue homogenate was prepared in 5 ml cryovials using a homogenizer under constant cooling using an ice bath. Each skin tissue was homogenized for 30 - 90 seconds with approximately 19000 to 26000 rpm. After every run, the homogenizer probe was washed first with 70% v/v isopropyl alcohol followed by PBS (pH 7.4). The probe was then wiped with a dry tissue paper before the next run. Homogenized samples were centrifuged at 10,000 rpm for 10 min at 4° C. The resulting supernatant was separated in micro centrifuge tube and snap frozen in liquid nitrogen and stored in -70° C. Cytokines like IL-4, TNF-α and IFN-Υ were estimated in skin homogenate supernatant using mouse ELISA kits (R&D systems). Cytokine levels were normalized to the amount of total proteins as determined by Bicinchoninic acid assay.

TABLE 2 Levels of Cytokines (IL-4, TNF-α and IFN-Y) ng/gm of Protein in Back Skin Homogenate after Montelukast Topical Cream and Montelukast Topical Gel Treatment (from day 6 to 14) in DNCB-induced Atopic Dermatitis in Balb/c Mice on day 15, n=10 Group No Dose Groups Ng/gm of protein in back skin homogenate (MEAN ± SD) IL-4 TNF-α IFN- γ 1 Normal Control 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 2 Disease Control 19.14 ± 7.67*** 8.28 ± 3.36*** 1.40 ± 0.58** 3 Placebo of Montelukast Sodium topical gel of Example 1 17.79 ± 9.25 6.68 ± 4.34 1.74 ± 0.27 4 Montelukast sodium topical gel of Example 1 18.99 ± 6.64 4.37 ± 1.94 1.29 ± 0.31^($$) 5 Placebo of Montelukast Sodium cream of Example 14 16.82 ± 3.80 5.28 ± 3.49 1.75 ± 0.74 6 Montelukast sodium topical cream of Example 14 18.20 ± 9.72 4.42 ± 3.62 1.67 ± 0.68 7 Betamethasone valerate cream IP 3.06 ± 1.35^(###) 4.96 ± 4.53 0.73 ± 0.26^(##) Data were analyzed by 2-tailed Student’s t-test

-   Normal Control vs Disease control group (*=p<0.05, **=p<0.01,     ***=p<0.001) -   Disease control group vs Betamethasone Valerate cream (#=p<0.05,     ##=p<0.01, ###=p<0.001) -   Placebo of Montelukast Sodium gel vs Montelukast Sodium gel     ($=p<0.05, $$=p<0.01, $$$=p<0.001) -   Placebo of Montelukast Sodium cream vs Montelukast Sodium cream     (@=p<0.05, @ @=p<0.01, @ @ @=p<0.001)

As seen in Table 2, the topical application of dinitrochloro benzene increased the levels of cytokines such as IL-4, TNF-α and IFN-γ in the disease control group as compared to the normal control group. Montelukast sodium topical gel showed significant inhibition in IFN-γ levels in skin homogenate as compared to its placebo. Betamethasone Cream showed significant inhibition in IL-4 and IFN-Υ levels in skin homogenate but did not show significant inhibition in TNF-α level as compared to disease control group. (FIG. 3 )

Immunohistochemistry (Ki67) Evaluation-

Images were captured from hematoxylin and cosin (H and E) stained skin sections at a magnification of 100X using ZEISS AxioAl microscope. The unstained sections were processed for immunohistochemistry of Ki67 marker using Ki67 Immunohistochemistry Kit (Eton Bioscience,Inc). The images were captured using ZEISS AxioAl microscope at 100X magnification.

The Ki67 is a cellular marker for proliferation and is associated with cell proliferation.

The immunohistochemistry in FIG. 4 demonstrates strong Ki67 staining in the back skin sections of disease control groups as compared to the normal control groups. Weak Ki67 staining was observed in the group treated with Betamethasone valerate cream as compared to the disease control group. Placebos of Montelukast sodium topical gel and Montelukast sodium topical cream showed strong staining of Ki67 comparable to the disease control group. However, Montelukast sodium gel showed moderate Ki67 staining as compared to its placebo. Also, it also showed moderate staining as compared to the disease control group. Thus, cell proliferation was less pronounced in the group treated with Montelukast sodium topical gel as compared to its placebo and the disease control group.

Example 16 . In Vitro Skin Permeation Studies

The in vitro skin permeation studies were determined using vertical static Franz cells. Two pieces of excised heat -separated human skin were used in this study. A total of 10 cells were used for each formulation with an average application of 14.07±2.5 mg/cm². 4.5 ml receptor solution was used in this study. The receptor solution was a mixture 30% Ethanol in Phosphate buffer saline. The receptor solution was sampled at 6 time points in addition to t₀. After 24 hours, the skin surface was washed using pre-developed washing procedure), the skin surface was then tape stripped (≤10 time). Both, the tape strips and skin were extracted with 3ml and 2 ml in 80% ethanol in water, respectively, for 24 hours under agitation. Wash, tape, skin and permeation samples were analyzed to determined mass balance. Total recoveries only were corrected for the assay.

Results indicated that more than 80% of the applied formulations were recovered on the skin surface. Formulation Montelukast sodium gel (example 1) and substantially anhydrous topical solution (example 13) showed higher depositions in the stratum corneum (SC) and skin compared to the cream formulation (example 14). Specifically, between about 0.5% to about 1% of Montelukast was deposited within the skin including the SC in the gel formulation and the anhydrous solution.

The safety, tolerability, pharmacokinetics and bioavailability of topical montelukast arc assessed according to methods well known in the art, for example according to

Cheng H, Leff JA, Amin R, Gertz BJ, De Smet M, Noonan N, Rogers JD, Malbecq W, Meisner D, Somers G. Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.Pharm Res. 1996 Mar; 13(3):445-8.

Example 17. Combination Product

Montelukast is combined with anti-pruritic /anti histamines/anti-inflammatory /anti-bacterial agents/vitamines (e.gpramoxine, hydrocortisone, desoximetasone, dapsone, minocycline vitamine E /B /C /D etc.,) and tested as described above. 

1. A topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof, a gelling agent and water for the treatment of atopic dermatitis.
 2. The topical formulation of claim 1, wherein the concentration of Montelukast tor its pharmaceutically acceptable salt is between about 0.5 % w/w to about 5 % w/w or between about 5 % w/w to about 10 % w/w.
 3. The topical formulation of claim 1, wherein the concentration of montelukast or a pharmaceutically acceptable salt is 5 %w/w.
 4. The topical formulation of claim 1, wherein between about 0.5% to about 1% of Montelukast is deposited within the skin following topical application.
 5. The topical formulation of claim 1, wherein the pH of the formulation is less than
 6. 6. The topical formulation of claim 1, wherein the pH is in the range 5 to
 6. 7. The topical formulation of claim 1, wherein the formulation further comprises a water miscible organic solvent.
 8. The topical formulation of claim 1, wherein the formulation further comprises a penetration enhancer.
 9. The topical formulation of claim 1, wherein the formulation further comprises an antioxidant.
 10. The topical formulation of claim 1, wherein the formulation further comprises a preservative.
 11. The topical formulation of claim 1 comprising: a) Category Ingredient Active Montelukast sodium Water miscible organic solvent Alcohol 96% Penetration enhancer DMSO Antioxidant BHT

Chelating Agent EDTA Water Purified water Preservative Methyl paraben Preservative Propyl paraben Gelling agent Hydroxyethylcellulose (M_(w)90,000 to 1,300,000) pH adjusting agent HCl (10% solution)

b) Category of ingredient Example of Ingredient Occlusive ingredient Dimethicone Occlusive ingredient Cyclomethicone Active Montelukast sodium Emulsifier Silicone Glycerol emulsifier Occlusive ingredient Cetearyl Ethylhexanoate Water miscible organic solvent Glycerin Solvent Water Gelling agent Sodium Carbomer Lubricant Sodium Hyaluronate

c) Category of ingredient Example of Ingredient Active Montelukast sodium Water miscible organic solvent Alcohol Antioxidant BHT Water Purified water Penetration enhancer DMSO Preservative Methyl paraben Preservative Propyl paraben Gelling agent Carbopol 947P(polymers of acrylic acid) Chelating agent EDTA Emulsifier/Thickener/Stabilizer Sepineo 600 (Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80)

d) Category of ingredient Example of Ingredient Active Montelukast sodium Water miscible organic solvent Alcohol Antioxidant BHT Water Purified water Penetration enhancer DMSO Preservative Methyl paraben Preservative Propyl paraben Gelling agent Carbopol 947P(polymers of acrylic acid) Chelating agent EDTA Emulsifier/Thickener/Stabilizer Sepineo 600(Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80) pH adjusting agent Phosphate or citric acid Buffer

.
 12. A topical formulation as in claim 11 selected from any one of the following a) Category Ingredient % W/W Active Montelukast sodium 5.00 Water miscible organic solvent Alcohol 96% 25.00 Penetration enhancer DMSO 10.00 Antioxidant BHT 0.10 Chelating Agent EDTA 0.10 Water Purified water 57.90 Preservative Methyl paraben 0.30 Preservative Propyl paraben 0.10 Gelling agent Hydroxyethylcellulose (M_(w) 90,000 to 1,300,000) 1.50 pH adjusting agent HCl (10% solution) q.s.

b) Category of ingredient Ingredient % W/W Occlusive ingredient Dimethicone 1 Occlusive ingredient Cyclomethicone 4 Active Montelukast sodium 3 Emulsifier Silicone Glycerol emulsifier 1.5

Occlusive ingredient Cetearyl Ethylhexanoate 2.5 Water miscible organic solvent Glycerin 3.0 Solvent Water Up to 100 Gelling agent Sodium Carbomer 2.5 Lubricant Sodium Hyaluronate 1.0

c) Category of ingredient Ingredient % W/W Active Montelukast sodium 1% Water miscible organic solvent Alcohol 25% Antioxidant BHT 0.10% Water Purified water 60.00 Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 0.40% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 (Acrylamide /Sodium Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 3%

d) Category of ingredient Ingredient % W/W Active Montelukast sodium 1% Water miscible organic solvent Alcohol 25% Antioxidant BHT 0.10% Water Purified water 60.00 Penetration enhancer DMSO 10.00% Preservative Methyl paraben 0.30% Preservative Propyl paraben 0.10% Gelling agent Carbopol 947P (polymers of acrylic acid) 0.40% Chelating agent EDTA 0.10% Emulsifier/Thickener/Stabilizer Sepineo 600 ( Acrylamide /Sodium 3% Acryloyldimethyl Taurate copolymer /isohexadecane and Polysorbate 80 pH adjusting agent Phosphate Buffer pH 5.6

.
 13. The topical formulation of claim 1, wherein the montelukast is homogeneously suspended in the formulation or wherein montelukast crystals are present in the formulation.
 14. A topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof and at least one oil for the treatment of atopic dermatitis wherein the formulation is waterless.
 15. A topical formulation as in claim 14 wherein the formulation further comprises a topically acceptable solvent, and an amphiphilic compound and further an occlusive ingredient.
 16. A topical formulation as in claim 15 selected from any of the following : a solution comprising Category of ingredient Example Topically acceptable solvent Alcohol (Dehydrated) Amphiphilic compound Poloxylhydrogenated Castor oil Active Montelukast sodium Oil Fractionated Coconut oil

or a gel formulation comprising Category of ingredient Example of ingredient Topically acceptable solvent Alcohol (Dehydrated) Amphiphilic compound Poloxylhydrogenated Castor oil Active Montelukast sodium Oil Fractionated Coconut oil Gelling agent Hydroxypropylcellulose

or an ointment comprising Category of ingredient Example of Ingredient Active Montelukast sodium Occlusive ingredient Petroleum jelly/white petrolatum Oil Trihydroxystearin Oil Olive oil

or an ointment comprising Category of ingredient Example of Ingredient Active Montelukast sodium Water miscible organic solvent Glycerine Oil Medium chain triglycerides Antioxidant Antioxidant

or an ointment comprising Category of ingredient Example of Ingredient Active Montelukast Sodium Antioxidant BHT Occlusive ingredient Cyclomethicone 5, NF Occlusive ingredient Cyclomethicone and Dimethicone 5225C

or an ointment comprising Category of ingredient Example of Ingredient Active Montelukast Sodium Antioxidant BHT Occlusive ingredient Petrolatum White USP Amphiphilic compound Propylene Glycol-15 Stearyl Ether Oil Medium Chain Triglycerides Amphiphilic compound Monosteol(propylene glycol monostearate)

or an ointment comprising Category of ingredient Example of Ingredient Active Montelukast Sodium Antioxidant BHT Occlusive ingredient/ Petrolatum White USP Oil Mineral Oil

.
 17. A topical formulation as in claim 16 selected from any one of the following: a solution comprising Category of Ingredient Ingredient % W/W Topically acceptable Alcohol (Dehydrated) 34.5 Amphiphilic compound Poloxylhydrogenated Castor 2.5 Active Montelukast sodium 3 oil Fractionated Coconut oil 60

or a gel formulation comprising Category of ingredient Ingredient % W/W Topically acceptable solvent Alcohol (Dehydrated) 31 Amphiphilic compound Poloxylhydrogenated Castor 2.5 Active Montelukast sodium 3 oil Fractionated Coconut oil 60 Gelling agent Hydroxy propyl cellulose 3.5

. or an ointment comprising Category of ingredient Ingredient % W/W Active Montelukast sodium 0.5-5 Occlusive ingredient Petroleum jelly/white petrolatum 80 Oil Trihydroxystcarin 1 -3 oil Olive oil 12- 18.5

or an ointment comprising Category of ingredient Ingredient % W/W′ Active Montelukast sodium 0.5-5 Water miscible organic solvent Glycerine 65-75 Oil Medium chain triglycerides 20 Antioxidant Antioxidant 0-0.5

or an ointment comprising Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient Cyclomethicone 94.52 Amphiphilic compound Cyclomethicone and Dimethicone 0.40

or an ointment comprising Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient Petrolatum White 55.92 Amphiphilic compound PPG-15 Stearyl Ether 16 Oil Medium Chain Triglycerides 20 Amphiphilic compound Monostcol 3

or an ointment comprising Category of ingredient Ingredient % W/W′ Active Montelukast Sodium 5 Antioxidant BHT 0.08 Occlusive ingredient/ Petrolatum White 49.92 Oil Mineral Oil 45

. 